Structural insight into SARS-CoV-2 neutralizing antibodies and modulation of syncytia.
Structural insight into SARS-CoV-2 neutralizing antibodies and modulation of syncytia.
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SARS-COV-2中和抗体的结构洞察力和合成的调节。
DOI：
10.1016/j.cell.2021.04.033
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发表时间：
2021-06-10
期刊：
影响因子：
64.5
通讯作者：
Wang CI
中科院分区：
文献类型：
--
作者：
Asarnow D;Wang B;Lee WH;Hu Y;Huang CW;Faust B;Ng PML;Ngoh EZX;Bohn M;Bulkley D;Pizzorno A;Ary B;Tan HC;Lee CY;Minhat RA;Terrier O;Soh MK;Teo FJ;Yeap YYC;Seah SGK;Chan CEZ;Connelly E;Young NJ;Maurer-Stroh S;Renia L;Hanson BJ;Rosa-Calatrava M;Manglik A;Cheng Y;Craik CS;Wang CI
严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的感染是通过病毒刺突蛋白与宿主受体血管紧张素转换酶 2 (ACE2) 结合启动的，随后病毒与宿主膜融合。尽管阻断这种相互作用的抗体已紧急用作 2019 年冠状病毒病 (COVID-19) 早期疗法，但中和效力的精确决定因素仍然未知。我们发现了一系列抗体，它们可以有效阻断 ACE2 结合，但对活病毒表现出不同的中和功效。引人注目的是，这些中和抗体可以抑制或增强 Spike 介导的膜融合和合胞体形成，这与 COVID-19 个体的慢性组织损伤有关。冷冻电镜显示，Spike-抗体复合物的多种结构具有不同的结合模式，不仅阻断 ACE2 结合，而且改变 ACE2 结合触发的 Spike 蛋白构象循环。我们表明，不同 Spike 构象的稳定会导致 Spike 介导的膜融合的调节，对 COVID-19 病理学和免疫产生深远影响。研究发现一系列针对 SARS-CoV-2 的抗体可有效阻断与宿主受体 ACE2 的结合，从而增强或抑制病毒 Spike 介导的膜融合和合胞体形成，这是 COVID-19 个体组织损伤的标志。
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is initiated by binding of the viral Spike protein to host receptor angiotensin-converting enzyme 2 (ACE2), followed by fusion of viral and host membranes. Although antibodies that block this interaction are in emergency use as early coronavirus disease 2019 (COVID-19) therapies, the precise determinants of neutralization potency remain unknown. We discovered a series of antibodies that potently block ACE2 binding but exhibit divergent neutralization efficacy against the live virus. Strikingly, these neutralizing antibodies can inhibit or enhance Spike-mediated membrane fusion and formation of syncytia, which are associated with chronic tissue damage in individuals with COVID-19. As revealed by cryoelectron microscopy, multiple structures of Spike-antibody complexes have distinct binding modes that not only block ACE2 binding but also alter the Spike protein conformational cycle triggered by ACE2 binding. We show that stabilization of different Spike conformations leads to modulation of Spike-mediated membrane fusion with profound implications for COVID-19 pathology and immunity. A series of antibodies against SARS-CoV-2 that potently block binding to the host receptor ACE2 are found to enhance or inhibit virus Spike-mediated membrane fusion and formation of syncytia, a sign of tissue damage in individuals with COVID-19.
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影响因子：
64.8
作者：
Barnes CO;Jette CA;Abernathy ME;Dam KA;Esswein SR;Gristick HB;Malyutin AG;Sharaf NG;Huey-Tubman KE;Lee YE;Robbiani DF;Nussenzweig MC;West AP Jr;Bjorkman PJ
通讯作者：
Bjorkman PJ
影响因子：
5.4
作者：
Huang, Kelly;Incognito, Len;Wu, Herren
通讯作者：
Wu, Herren
DOI：
10.1107/s2059798318006551
发表时间：
2018-06-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Poon BK;Read RJ;Sobolev OV;Terwilliger TC;Urzhumtsev A;Adams PD
通讯作者：
Adams PD
影响因子：
5.3
作者：
Goh AX;Bertin-Maghit S;Ping Yeo S;Ho AW;Derks H;Mortellaro A;Wang CI
通讯作者：
Wang CI
影响因子：
3.7
作者：
FLAMAND, A;RAUX, H;RUIGROK, RWH
通讯作者：
RUIGROK, RWH